The elimination of cells via programmed cell death is a prominent feature of normal development throughout the animal kingdom (Wyllie et al., Nature 284:555-557 (1980); Bowen and Lockshin, Cell Death in Biology and Pathology, Chapman and Hall (1981); Truman and Schwartz, J. Neurosci. 4:274 (1984); Ellis et al., Annu. Rev. Cell Biol. 7:663-698 (1991); Tomei and Cope, Apoptosis: The Molecular Basis of Cell Death, Cold Spring Harbor Laboratory Press, New York, (1991); Yuan and Horvitz, Dev. Biol. 138:33-41 (1990); Raff, Nature 356:397-400 (1992)). In many organisms, a large number of cells die in the absence of obvious external insults. For example, vertebrate neurogenesis produces about twice as many neurons as are needed in the mature nervous system, and approximately half of these neurons are eliminated by cell death (Cowan et al., Science 225:1258 (1984)). This "natural" death process occurs in a morphologically characteristic and reproducible way, referred to as apoptosis (Kerr et al., Br. J. Cancer 26:239-257 (1972); Kerr et al., Perspectives on Mammalian Cell Death (ed C. S. Potten), Oxford University Press, England, p. 93 (1987); Kerr and Harmon, Apoptosis: The Molecular Basis of Cell Death (eds. Tomei, L. D., and Cope, F. O.), Cold Spring Harbor Laboratory Press, New York, pp. 5-29 (1991); Lockshin and Zakeri, Apoptosis: The Molecular Basis of Cell Death (eds. Tomei, L. D., and Cope, F. O.), Cold Spring Harbor Laboratory Press, New York, p. 47-60 (1991)). During apoptotic death, the cytoplasm and nucleus of the dying cell condense, while the morphology of cellular organelles remains rather well preserved. In many cases, the cell breaks up into fragments (apoptotic bodies) and is eventually engulfed by phagocytic cells. In contrast, externally induced cellular injury (e.g., as the result of temperature shocks, lack of oxygen, some toxic chemicals) results in necrosis (reviewed by Kerr and Harmon, Apoptosis: The Molecular Basis of Cell Death (eds. Tomei, L. D., and Cope, F. O.), Cold Spring Harbor Laboratory Press, New York, pp. 5-29 (1991)). Necrotic deaths are characterized by a general swelling of the cell and its organelles, loss of membrane integrity, lysosomal rupture and cellular disintegration.
It is now generally supposed that apoptosis is the result of an active cellular program, comparable to cell differentiation. In some cases, this developmental program of cell death appears to be triggered by systemic hormones, trophic factors, and local cell interactions (Truman, Ann. Rev. Neurosci. 7:171-188 (1984); Oppenheim, Trends Neurosci. 8:487-493 (1985); Campos, A. R. et al., Development 114:355-366 (1992)). In many instances, apoptotic deaths have been found to depend on RNA and protein synthesis within the dying cell (Martin et al., J. Cell Biol. 106:829-844 (1988); Oppenheim et al., Dev. Biol. 138:104-113 (1990); Fahrbach and Truman, Soc. Neurosci. Abst. 14:368 (1988); Kimura and Truman, J. Neurosci. 10:403-411 (1990); Scott and Davies, J. Neurobiol. 21:630 (1990)), suggesting that the activity of genes is required for controlling and/or executing programmed cell death. However, despite its importance in animal development, little is known about the genetic and molecular mechanisms underlying programmed cell death.